Opioid and opioid-like compounds and uses thereof

ABSTRACT

The present invention relates to opioid and opioid-like compounds, and pharmaceutical formulations thereof, and use thereof for prevention and treatment of disorders such as septic shock and organ damage.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in part of application Ser. No 10/936,431 filedon Sep. 8, 2004 which claims the benefit of U.S. Provisional ApplicationSer. 60/518,448 filed on Nov. 7, 2003 and is a continuation-in-part ofInternational Application PCT/US03/15461 filed on May 16, 2003 whichdesignated the U.S. and claims the benefit of U.S. ProvisionalApplication No. 60/380841 filed May 17, 2002and incorporates all of theabove by reference.

FIELD OF THE INVENTION

The present invention relates to opioid and opioid-like compounds, andpharmaceutical formulations thereof, and use thereof for prevention andtreatment of disorders such as septic shock and organ damage.

BACKGROUND OF THE INVENTION

Morphine is a known analgesic compound isolated from the opium poppy andhas the following structural formula:

Although morphine is a potent analgesic, it possesses severalundesirable side effects, including, but not limited to, physicaldependence. Therefore, several compounds have been developed by additionor substitution to the basic morphine skeleton. Several such compoundsare described in U.S. Pat. No. 5,219,347, issued Jun. 15, 1993 toKanematsu, et al.; U.S. Pat. Nos. 5,912,347 and 6,242,604, issued Jun.15, 1999 and Jun. 5, 2001 to Hudlicky et al.; U.S. Pat. No. 6,150,524,issued Nov. 21, 2000 to Hartmann et al.; U.S. Pat. No. 6,323,212, issuedNov. 27, 2001 to Nagese et al. and European Patent No. 577,847,published Jan. 12, 1994; European Patent No. 242,417, published Feb. 10,1993; and European Patent No. 632,041, published Jan. 4, 1995. When amethoxy group is substituted for the 3-hydroxyl group, the compound iscodeine, an opioid often used as an analgesic and also in coughmedications for its antitussive effects.

Various substituents of the morphine structure are not required for anarcotic effect. Such morphine derivatives are classed as morphinans. Asused in the present application, a morphinan is a compound similar tomorphine but lacks the 4,5-ether, and may also lack the 7,8 alkenylbond, and has the following structural formula:

The numbering system used with compound (II) is a “conventionalnumbering system used in describing morphinans and corresponds to thenumbering of morphine (I) used above. It is recognized that theInternational Union of Pure and Applied Chemistry (IUPAC) numberingsystem is different, so that, e.g., the Merck Index (12 ed., 1996) namesthe compound Morphinan in monograph 6358 at pp. 1073-74 as [4aR(4aα,10α, 10aα)]-1,3,4,9,10,10a-Hexahydro-2H-10,4a-iminoethano) phenanthreneand has the following structural formula:

In the present application, the “conventional” numbering system is usedunless otherwise noted.

Some morphinans are agonists, producing an analgesic effect while othermorphinans are antagonists, blocking the effect of morphine and morphineagonists. Still other morphinans exhibit a combined agonist/antagonistactivity, producing an analgesic effect itself while blocking theagonist activity of other morphinans. Finally, some morphinans,including the compound morphinan (IIa), exhibit no biological activity.The so-called “morphine rule,” or Becket-Casey rule, requires (1) anaromatic ring (2) attached to a quaternary center which is connected to(3) a tertiary nitrogen which is (4) located two carbon atoms away. Ithas been found that substitution of the nitrogen methyl group by allyl,n-propyl, a substituted allyl, propynyl, cyclopropyl methyl, andcyclobutyl methyl results in morphine antagonists.

Representative morphinans are shown in the following patents: U.S. Pat.No. 3,275,638, issued Sep. 27, 1966 to Sawa et al.; U.S. Pat. No.3,819,635, issued Jun. 25, 1974 to Pachter et al.; U.S. Pat. No.4,228,285, issued Oct. 14, 1980; U.S. Pat. No. 4,673,679, issued Jun.16, 1987 to Aungst et al.; U.S. Pat. No. 4,912,114, issued Mar. 27, 1990to L. Revesz and U.K. Patent No. 2,175,898, published Dec. 10, 1986;U.S. Pat. No. 5,071,985, issued Dec. 10, 1991 to Andre et al.; U.S. Pat.No. 5,504,208, issued Apr. 2, 1996 to Sobotik et al.; U.S. Pat. No.6,166,211, issued Dec. 26, 2000 to Cain et al.; and U.K. Patent No.1,038,732, published Aug. 2, 1967.

A further simplification of the morphine structure involves eliminationof one of the cycloalkane rings to produce 6,7 benzomorphans having thestructural formula:

Representative benzomorphans are shown in the following patents: U.S.Pat. No. 3,764,606, issued Oct. 9, 1973 to Akkerman et al.; U.S. Pat.No. 3,936,463, issued Feb. 3, 1976 to Behner et al.; U.S. Pat. No.4,029,798, issued Jun. 14, 1977 to Yamamoto et al.; U.S. Pat. No.4,128,548, issued Dec. 5, 1978to Akkerman et al.; U.S. Pat. No.4,288,444, issued Sep. 8, 1981 to Akkerman et al.; U.S. Pat. No.5,354,758, issued Oct. 11, 1994 to Lawson et al.; U.S. Pat. Nos.5,607,941, issued Mar. 4, 1997 to Merz et al., 5,731,318, issued Mar.24, 1998to Carter et al., and Canadian Patent No. 2,072,814, publishedJan. 3, 1993; U.K. Patent No. 1,077,711, published Aug. 2, 1967.

Another class of morphine derivatives, the morphones, feature anoxidized oxygen atom at C6, and have the following structural formula:

Representative morphone compounds are described in the followingpatents: U.S. Pat. No. 4,230,712, issued Oct. 28, 1980 to Kotick et al.;U.S. Pat. No. 4,272,541, issued Jun. 9, 1981, also to Kotick et al.;U.S. Pat. No. 4,388,463, issued Jun. 14, 1983 to Brossi et al.; U.S.Pat. No. 4,390,699, issued Jun. 28, 1983, also to Brossi et al.; U.S.Pat. No. 5,780,479, issued Jul. 14, 1998 to S. W. Kim; and U.S. Pat. No.6,271,239, issued Aug. 7, 2001 to Portoghese et al.

EP 377272 (Baker Cummin Pharma) discloses nalmefene and naltrexone fortreatment in arthritic and inflammatory diseases.

U.S. Pat. No. 4,267,182 (Holaday et al) discloses the use of naloxone,natltrexone, nalorphine, diprenorphine, lavallorphan, pentazocine,metazocine, cyclazocine and etazocine for treatment of shock.

WO 98/05667 (Johnson Matthey) describes the production of hydrocodoneand hydromorphone.

WO 02/16367 (Glaxo Wellcome Australia) describes N-demethylatingN-morphinanes to produce intermadiates that can be used to replace themethyl group with groups such as allyl and cyclopropylmethyl groups.

WO 02/36573 ((Rensselaer Polytrchnic) describes varipous benzazocineswhich are useful as analgesics, anyi-diarrheal agents, anticonvulsants,antitussives and anti-addiction agents.

WO 00/56735 (Endo Pharmaceuticals) describes the production of 10-ketoderivatives from morphians such as naloxone.

J. Org Chem vol 49 (June 1984) pages 2081-2 describes an improvedsynthesis of naltrexone and nalbuphine”

Schmidhammer etal J. Med. Chem. 27 (No 12) 1575-1579 (1984) describesoxymorphone and its 3-benzyloxy analog.

Coop et al. Bioorganic & Medicianl Chemistry Letters vol 9 pages 3435-8(1999) compounds similar to those of structure V of the presentinvention but wherein wherein X is cyclopropylmethyl and R is hydrogen,bezyl, phenylethyl or phenylpropyl.

German 2238839 (Boehringer, Sohn and Ingelheim) describes the productionof compounds similar to those of formula VII of the present inventionwherein R as set out in formula VII is hydrogen, methyl or acetyl andour X as furyl methyl or thienyl methyl.

U.S. Pat. No. 4,161,597 (Olofson) describes reactions of14-hydroxymorphinans.

WO 03/037340 (Pain Therapeutics), describes the use of opioid inhibitorsin increasing efficiency of certain anti-tumor agents. Compounds ofstructure V of the present invention where R is hydrogen and groups inthe position corresponding to X are cycloalkylalkyl, allyl, or arylalkylare included.

EP 663401 (Toray) describes an extremely large number of morphinanderivatives for use as analgesics, diuretics, antitussives and braincell protective agents.

Filer et al J. Org. Chem. Vol 46 pages 4968-70 describes compoundssimilar to those of formula V of the present invention wherein R ishydrogen and our X is allyl or methyl ethynyl.

Jacobson et al J. Med. Chem. Vol 22 No.3 pages 328-331 (1979) describescompounds similar to those of structure V of the present invention withR as hydrogen and X is hydrogen or ethylene nitrile.

Koolpe et al J. Med. Chem. Vol 27 pages 1718-23 (1984) discussesnaltrexone and oxymorphone binding mechanisms.

Previous work in this area has generally focused upon the investigationof the use of these morphine derivatives as analgesics, morphineantagonists, or antitussives. However, recent literature has reportedpotential new uses for some morphine derivatives which may not bemediated through morphine receptors. A series of compounds that aremodified in position 3 and 17 of the morphinan ring system have beenreported to exhibit anticonvulsant effects in Bioorg. Med. Chem. Lett.11, 1651-1654 (2001). A series of stereoisomer 6,7-benzomorphanderivatives with modified N-substituents are described in J. Med. Chem.40, 2922-2930 (1997) as antagonizing the N-methyl-D-aspartate (NMDA)receptor-channel complex in vitro and in vivo. (+)-Pentazocine, a sigmareceptor agonist, has been demonstrated to have unique survival activityon cortical neurons through sigma receptors in Cell. Mol. Neurobiol.20(6), 695-702 (2000). Two homologs in the (+)-(1S,5S,9S)-normetazocineseries, N-pent-4-enyl and N-hex-5-enyl, are reported in J. Med. Chem.43(26), 5030-5036 (2000), to have high-affinity and selective σ1-ligands(Ki=2 nM, σ2/σ1=1250, and 1 nM, σ2/σ1 =750, resp.); in contrast,N-allylnormetazocine has relatively poor affinity at σ1, and its σ1/σ2ratio is <100.

Recent advances in the research of neurodegenerative diseases of thecentral nervous system have revealed that the opioids may play a role inmodulating the expression of inflammatory factors such asproinflammatory cytokines, free radicals and metabolites of arachidonicacid in microglia and in the mediation of immune-relatedneurodegeneration, Adv. Exp. Med. Biol. 402:29-33 (1996); Mov. Disord.12:855-858 (1997). Naloxone, a morphine antagonist, is disclosed in J.Pharmacol. Exp. Therap. 293, 607-617 (2000) to protect rat dopaminergicneurons against inflammatory damage through inhibition of microgliaactivation and superoxide generation.

The potential for the development of tolerance and physical dependencewith repeated opioid use is a characteristic feature of all the opioiddrugs, and the possibility of developing psychological dependence (i.e.,addiction) is one of the major concerns in the use of the treatment ofpain with opioids. Another major concern associated with the use ofopioids is the diversion of these drugs from the patient in pain toanother (non-patient) for recreational purposes, e.g., to an addict.Thus, it is desirable to provide opioid and opioid-like compounds usefulfor the prevention or treatment of various disorders as describedherein.

Aerobic organisms, which derive their energy from the reduction ofoxygen, are susceptible to the damaging actions of the small amounts ofO₂—, OH and H₂O₂ that inevitably form during the metabolism of oxygen,especially in the reduction of oxygen by the electron transfer system ofmitochondria. These three species, together with unstable intermediatesin the peroxidation of lipids, are referred to as Reactive OxygenSpecies (ROS). Many diseases such as, but not limited to, Alzheimer'sDisease, Parkinson's disease, aging, cancer, myocardial infarction,atherosclerosis, autoimmune diseases, radiation injury, emphysema,sunburn, and joint disease (a. Everything cytokine & beyond, CytokinesMini-Reviews, Chapter:Reactive Oxygen Species (ROS), Copyright 2003 ©R&DSystems; b. Channon K M, Guzik T J, Mechanisms of superoxide productionin human blood vessels: relationship to endothelial dysfunction,clinical and genetic risk factors. J. Physiol. Pharmacol. 2002, 53(4),515-524; c. Henrotin, Y E et al. The role of reactive oxygen species inhomeostasis and degradation of cartilage. OsteoArthritis and Cartilage2003, 11, 747-755; d. Arzimanoglou A et al. Epilepsy andneuroprotection: An illustrated review article. Epileptic Disord 2002,3,173-82; e. Seidman M D et al., Biologic activity of mitochondrialmetabolites on aging and age-related hearing loss.

Am J Otol 2000, 21(2):161-7.) are linked to damage from ROS as a resultof an imbalance between radical-generating and radical-scavengingsystems—a condition called oxidative stress. The discovery by McCord andFridovich (McCord, J. M. & I. Fridovich J. Biol. Chem. 1969, 244:6049)of the superoxide dismulase (SOD) activity of erythrocuprein, togetherwith the finding that almost all mammalian cells contain SOD, suggests aphysiological role of at least the central ROS, superoxide.

TNF-α (tissue necrosis factor), a cytokine that plays a critical role ineliciting the body's inflammatory response and is present in abnormallyhigh levels in the joints of individuals suffering from rheumatoidarthritis, has been implicated as an immune modulator in the immunesystem. Inhibitors of TNF-α have been shown to halt the progression ofcartilage destruction and relieve the symptoms of severe arthritis.Approximately 30% of moderate to severe arthritic patients are notresponsive to these treatments (Feldman M, Maini R N, Discovery of TNF-αas a therapeutic target in rheumatoid arthritis: preclinical andclinical studies. Joint Bone Spine 2002, 69, 12-18; Lipsky P E, et al.Infliximab and methotrexate in the treatment of rheumatoid arthritis. N.Engl. J. Med. 2000, 343 1954-1602). Animal studies in association withstudies conducted in humans indicate a potential role for TNF modulationin Crohn's disease, ulcerative colitis, insulin resistance, multiplesclerosis, multiple organ failure, pulmonary fibrosis, andatherosclerosis (Newton R C, Decicco C P, Therapeutic potential andstrategies for inhibiting tumor necrosis factor-a. J. Med. Chem. 1999,42, 2295-2314). Biswas P, et al. reported that TNF-α drives HIV-1replication in U937 cell clones (Biswas P, et al. Tumor necrosisfactor-alpha drives HIV-1 replication in U937 cell clones andupregulates CXCR4. Cytokine. 2001, 13, 55-59). Liver damages areassociated with TNF-α release have been reported recently (McClain C J,et al. Advances in Alcoholic Liver Disease, Current GastroenterologyReports, 2004, 6, 71- 76).

During the course of sepsis, nitric oxide (NO) is produced. Itsmetabolites impair normal vascular reactivity, in conjunction withelevated endotoxin levels. Inhibitors of NO synthase restore bloodpressure, lower the cardiac index and increase pulmonary and systemicvascular resistance. Selective NOS inhibitors targeted against iNOS mayprove to be beneficial. A small study with an inhibitor of NOS action,namely methylene blue, which inhibits the associated guanylyl cyclaseenzyme, has indicated beneficial effects versus the cardiovascularparameters described above in patients with septic shock [Preiser, J C,Lejeune P, Roman A, et al. Methylene blue administration in septicshock: a clinical trial. Crit. Care Med., 23: 259-64(1995); Gachot B,Bedos J P, Veber B, et al. Short term effects of methylene blue onhemodynamics and gas exchange in humans with septic shock, IntensiveCare Med 21:1027-31; Vincent, J L, Sun Q, Dubois, M-J, Clinical Trialsof Immunomodulatory Therapies in Severe Sepsis and Septic Shock, CID,34: 1084-1093 (2002)].

SUMMARY OF THE INVENTION

According to embodiments of the present invention, the present inventionrelates to a compound according to the formula R-A-X wherein:

R can be H, alkyl, allyl, phenyl, benzyl, or (CH₂)_(m)R₄, wherein m isfrom 0 to 6, and R₄ can be a ring structure. Such ring structures canbe, for example, phenyl, naphthyl, and biphenyl, wherein the ring isoptionally substituted with one to three substituents selected from thegroup consisting of halogen, alkyl, NO₂, CN, CF₃, and lower alkoxy R₄can be a five-membered heterocyclic ring having one or more heteroatomsselected from the group consisting of O, S, and N, wherein theheterocyclic ring is substituted with a lower alkyl or a substitutedphenyl group; R₄ can be a pyridine ring wherein the pyridine ring isoptionally substituted with halogen, alkyl, NO₂, CN, CF₃, OCH₃, orNR₁R₂, where R₁ and R₂ are each independently H or alkyl, or R₁ and R₂together with the nitrogen to which they are bound jointly form a cyclicring, wherein the cyclic ring is a 3- to 7- membered alicyclic ringoptionally having a double bond in the ring. R₄ can be quinoline. R₄ canbe isoquinoline. R₄ can be 4-cyclohexylphenyl. R₄ can be a cyclic ring,wherein the cyclic ring is a 3- to 7-membered alicyclic ring optionallyhaving a double bond in the ring;

A can be a structure such as one of the following structures:

X can be hydrogen, allyl, cinnamoyl, crotonyl, (CH₂)C₆H₅-4F,(CH₂)_(n)C=CR₁R₂, (CH₂)_(n)≡CR₃, (CH₂)_(n)R₅, and (CH₂)_(m)CHR₆R₇,wherein m is 0 to 6 and and n is from 0 to 6. R₃ can be H, alkyl, or thesame as R₄, wherein R₄ is described above and R₅ can be alkyl, CN, COR₈,or structures selected from the group consisting of the followingstructures:

wherein Y can be O, S or N. R₆ and R₇ are each independently the same asR₄ as defined above; and R₈ is alkyl, the same as R₄ as defined above,or the same as R₅ when R₅ can be the structures described above(IX-XVIII). The novel compounds according to the formula R-A-X can beenantiomers, diastereoisomers, and pharmaceutically acceptable saltsthereof. According to some embodiments, when A is the structureaccording to formulas V, VI and VII, and R is H, alkyl, allyl, orbenzyl, X is not (CH₂)_(n)C═CR₁R₂, (CH₂)_(n)C≡CR₃, (CH₂)_(n)R₅, whereinn is from 0 to 6, R₁ and R₂ are described as above, R₃ is H, alkyl, orthe same as R₄, wherein R₄ is phenyl, and R₅ is alkyl, CN and COR₈,wherein R₈ is alkyl or the same as R₄, wherein R₄ is a five-memberedheterocyclic ring having one or more heteroatoms selected from the groupconsisting of O, S, and N.

Some compounds covered by the above formulae are known and we make noclaim to them. In particular we make no claim to compounds

i) where A is of structure V and Vb and

-   -   (a) R is hydrogen and X is allyl;    -   (b) R is methyl and X is methyl;    -   (c) R as hydrogen and X as methyl;    -   (d) R is hydrogen, methyl or ethyl and X is methyl;    -   (e) R as hydrogen or benzyl and X as methyl;    -   (f) R is hydrogen, methyl or acetyl and X is hydrogen;    -   (g) R is hydrogen and our X is allyl or methyl ethynyl;    -   (h) R is hydrogen and X is hydrogen or ethylene nitrile; group;    -   (i) R is hydrogen, methyl and X is phenyl;

ii) where A is formula VI and

-   -   (a) R is hydrogen, methyl or ethyl and X as methyl;    -   (b) R as hydrogen and X of our definition is allyl;    -   (c) R is hydrogen of C₁₋₄ alkyl and X is C₁₋₄ alkyl or alkenyl,        C₃₋₄ cycloalkyl, C₃₋₄ cycloalkyl alkyl or C₃₋₄ cycloalkyl        carbonyl;    -   (d) R is hydrogen of C₁₋₄ alkyl and X is C₁₋₄ alkyl or alkenyl,        C₃₋₄ cycloalkyl;

iii) where A is formula VII and

-   -   (a) R as hydrogen and X as allyl;    -   (b) R is hydrogen of C₁₋₄ alkyl and X is C₁₋₄ alkyl or alkenyl,        C₃₋₄ cycloalkyl, C₃₋₄ cycloalkyl alkyl or C₃₋₄ cycloalkyl        carbonyl; and

iv) where A is formula XIX and

R is hydrogen, C1-C3 alkyl, a five-membered heterocyclic group and X asmethyl, other alkyl, alkenylmethylene, arylymethyl, heterocyclylmethyl,or benzyl.

According to other embodiments of the present invention, the inventionrelates to methods of preventing or treating viral infections andconditions such as septic shock, inflammation, organ damage,neurological disorders, neurodegenerative diseases, cancer, cardiacdisorders, and diseases associated with overproduction of superoxideanion radical, TNF-α, or iNOS, comprising administering to a subject inneed thereof, a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of formula R-A-X described above.

According to still other embodiments, the present invention relates tomethods of preventing or treating viral infections and conditionsselected from the group consisting of septic shock, inflammation, organdamage, neurological disorders, neurodegenerative diseases, cancer, andcardiac disorders, and diseases associated with overprodcution orsuperoxide anion radical, TNF-α, or iNOS, comprising administering to asubject in need thereof, a pharmaceutical composition comprising atherapeutically effective amount of compound according to the formulaR-A-X wherein:

R is methyl;

A has the following structure:

and

X can be hydrogen, methyl, cyclobutyl (CH₂)₄, n-propyl, CN, allyl,CH₂═C(CH₂₎ ₂, or enantiomers, diastereoisomers, and pharmaceuticallyacceptable salts thereof.

According to yet other embodiments of the present invention, the presentinvention relates to methods of preventing or treating viral infectionsand conditions such as septic shock, organ damage, neurologicaldisorders, neurodegenerative diseases, cancer, and cardiac disorders,and diseases associated with overprodcution or superoxide anion radical,TNF-α, or iNOS, comprising administering to a subject in need thereof, apharmaceutical composition comprising a therapeutically effective amountof opioid and opioid-like compounds, and derivatives and analogsthereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates effects of XXV post-treatment on mean arterial bloodpressure (MAP) in rats treated with lipopolysaccharide (LPS).

FIG. 2 illustrates effects of XXV post-treatment on heart rate in ratstreated with lipopolysaccharide (LPS).

FIG. 3 illustrates effects of XXV treatment on plasma levels of serumglutamate-oxalate-transferase (SGOT) in rats treated withlipopolysaccharide (LPS).

FIG. 4 illustrates effects of XXV treatment on plasma levels of serumglutamic pyrate transaminase (SGPT) in rats treated withlipopolysaccharide (LPS).

FIG. 5 illustrates PMN filtration through histological studies of normallung tissues of rats receiving (A) XXVI alone, (B) injections oflipopolysaccharide (LPS), and (C) pretreatment with XXVI.

FIG. 6 illustrates effects on the alveolar wall through histologicalstudies of normal lung tissues of rats receiving (A) XXVI alone, (B)injections of lipopolysaccharide (LPS), and (C) pretreatment with XXVI.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The foregoing and other aspects of the present invention will now bedescribed in more detail with respect to other embodiments describedherein. It should be appreciated that the invention can be embodied indifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a”, “an” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

All publications, patent applications, patents and other referencescited herein are incorporated by reference in their entireties for theteachings relevant to the sentence and/or paragraph in which thereference is presented.

The term “alkyl” as used herein refers to C1-C20 inclusive, linear,branched, or cyclic, saturated or unsaturated hydrocarbon chains,including for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl,pentyl, hexenyl, octenyl, butadienyl, and allenyl groups. Alkyl groupscan either be unsubstituted or substituted with one or morenon-interfering substituents, e.g., halogen, alkoxy, acyloxy, hydroxy,mercapto, carboxy, benzyloxy, phenyl, benzyl, or other functionalitywhich has been suitably blocked with a protecting group so as to renderthe functionality non-interfering. Each substituent may be optionallysubstituted with additional non-interfering substituents. The term“non-interfering” characterizes the substituents as not adverselyaffecting any reactions to be performed in accordance with the processof this invention.

The term “lower alkyl” as used herein refers to C1 to C8 alkyl,including C1 to C3, C1 to C4, C1 to C5, C1 to C6, and C1 to C7, whichmay be linear or branched and saturated or unsaturated.

The term “cycloalkyl” as used herein is typically C3, C4 or C5 to C6 orC8 cycloalkyl.

The term “aryl” as used herein refers to C6 to C10 cyclic aromaticgroups such as phenyl, benzyl, naphthyl, and the like, and includessubstituted aryl groups such as tolyl.

The term “heterocycle” as used herein refers to a monovalent saturated,unsaturated, or aromatic carbocyclic group having a single ring ormultiple condensed ring and having at least one hetero atom, such as N,O, or S, within the ring, which can optionally be unsubstituted orsubstituted with hydroxy, alkyl, alkoxy, halo, mercapto, and othernon-interfering substituents. Examples of nitrogen heterocycles include,but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, and indoline.

The term “halo” as used herein refers to any halogen group, such aschloro, fluoro, bromo, or iodo.

The term “opioid” as used herein refers to compounds that exhibit opiumor morphine-like properties, including agonist and antagonist activitywherein such compounds can interact with stereospecific and saturablebinding sites in the brain and other tissues. Pharmacological propertieshave previously included drowsiness, respiratory depression, changes inmood and mental clouding without a resulting loss of consciousness. Theterm “opioid-like” as used herein refers to compounds that are similarin structure and/or pharmacological profile to known opioid compounds.Examples of opioid and opioid-like compounds, include but are notlimited to, endogenous opioid-like peptides that are presentparticularly in areas of the central nervous system, alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,desomorphine, dextromoramide, dextromethorphan, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, morphinan, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, naltrindole, nalorphine,naloxone, nalbuphene, nalmefene, naltrexone, normorphine, norpipanone,opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sufentanil,tilidine, tramadol, and derivatives and analogs thereof.

“Treat” or “treating” as used herein refers to any type of treatmentthat imparts a benefit to a patient afflicted with a disease, includingimprovement in the condition of the patient (e.g., in one or moresymptoms), delay in the progression of the condition, prevention ordelay of the onset of the disease, etc.

As used herein, a “pharmaceutically acceptable” component (such as asalt, carrier, excipient or diluent) means that the compound orcomposition is suitable for administration to a subject to achieve thetreatments described herein, without unduly deleterious side effects inlight of the severity of the disease and necessity of the treatment.

“Therapeutically effective amount” as used herein refers to an amountnecessary to prevent, delay or reduce the severity of the condition ofinterest and also includes an amount necessary to enhance normalphysiological functioning.

In general, active compounds of the present invention are novel opioidor opioid-like compounds. These novel compounds are useful forpreventing or treating diseases or disorders as described herein. Novelcompounds according to the present invention comprise a structureaccording to the formula R-A-X wherein:

R can be H, alkyl, or (CH₂)_(m)R₄, wherein m is from 0 to 6 and R₄ canbe a ring structure. The ring structure can be aryl including, but notlimited to, phenyl, benzyl, naphthyl, and biphenyl, wherein the ring isoptionally substituted with one to three substituents selected from thegroup consisting of halogen, alkyl, NO₂, CN, CF₃, and lower alkoxy. R₄can be a five-membered heterocyclic ring having one or more heteroatomsselected from the group consisting of O, S, and N, wherein theheterocyclic ring is substituted with a lower alkyl or a substitutedphenyl methyl group. R₄ can be a pyridine ring wherein the pyridine ringis optionally substituted with halogen, alkyl, NO₂, CN, CF₃, OCH₃, orNR₁R₂, where R₁ and R₂ are each independently H or alkyl, or R₁ and R₂is a cyclic ring, wherein the cyclic ring is a 3- to 7- memberedalicyclic ring optionally having a double bond in the ring. R₄ can bequinoline. R₄ can be isoquinoline. R₄ can be 4-cyclohexylphenyl. R₄ canbe a cyclic ring, wherein the cyclic ring is a 3- to 7-memberedalicyclic ring optionally having a double bond in the ring;

A can be a structure such as one of the following structures:

A can be a structure that has an opioid or opioid-like core structure orcan be modified to represent an opioid or opioid-like core structure.Such compounds that can provide a core structure include, but are notlimited to, alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dextromethorphan,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, morphinan, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,naloxone, nalbuphene, nalmefene, naltrexone, normorphine, norpipanone,opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sufentanil,tilidine, tramadol, and derivatives and analogs thereof, now known orlater identified.

X can be hydrogen, allyl, cinnamoyl, crotonyl, (CH₂)C₆H₅-4F,(CH₂)_(n)C═CR₁R₂, (CH₂)_(n)C≡CR₃, (CH₂)_(n)R₅, and (CH₂)_(m)CHR₆R₇,wherein m is from 0 to 6 and n is from 0 to 6. R₃ can be H, alkyl, orthe same as R₄, wherein R₄ is described above and R₅ can be alkyl, CN,COR₈, or structures selected from the group consisting of the followingstructures:

wherein Y can be O, S or N. R₆ and R₇ are each independently the same asR₄ as defined above; and R₈ is alkyl, the same as R₄ as defined above,or the same as R₅ when R₅ can be the structures described above(IX-XVIII).

When A is of the formula VII and the group (CH₂)_(n)C=R₁R₂ is cinnamyl,it may be appropriate that R is not H, alkyl, allyl or benzyl. Forexample, a compound of the present invention according to the formulaR-A-X can comprise the structure

where R and X are described herein. This example further illustrates theplacement of R and X, and thus, substitutents corresponding thereto.

The novel compounds described above do not encompass compounds currentlyknown as of the date of this invention.

Some of the compounds of the present invention described above canpossess narcotic and analgesic properties as well as antiviralactivities and inhibition of the release and production of superoxideanion TNF-α, and iNOS. However, certain therapeutic effects of thecompounds of the present invention can be mediated through mechanismsother than through interaction with opiate receptors. Novel compounds ofthe present invention described above can be useful for the preventionor treatment of viral infections and diseases, disorders and/orconditions such as septic shock, inflammation, organ damage,neurological disorders, cancer, cardiac disorders, and cardiacdisorders, and diseases associated with overproduction of superoxideanion radical, TNF-α, and iNOS, wherein a pharmaceutical compositioncomprising a therapeutically effective amount of the compound isadministered to a subject in need thereof.

Active compounds of the present invention further comprise the use ofopioid and opioid-like compounds, now known and later identified, forthe prevention and treatment of viral infections and diseases, disordersand/or conditions such as septic shock, organ damage, neurologicaldisorders, neurodegenerative diseases, cancer, and cardiac disorders,and diseases associated with overproduction of superoxide anion radical,TNF-α, and iNOS, wherein a pharmaceutical composition comprising atherapeutically effective amount of the compound is administered to asubject in need thereof. Examples of such opioid and opioid-likecompounds include, but are not limited to, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, desomorphine,dextromoramide, dextromethorphan, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, morphinan, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, naloxone, nalbuphene, nalmefene, naltrexone,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,propoxyphene, sufentanil, tilidine, tramadol, and derivatives andanalogs thereof, now known or later identified.

Active compounds of the present invention can be water soluble and canalso comprise known water-soluble opioid and opioid-like derivatives.

Compounds of the present invention can possess an asymmetric carbonatom(s) and therefore are capable of existing as enantiomers ordiastereoisomers. Thus, compounds of the present invention includeenantiomers and diastereoisomers as well as pharmaceutically acceptablesalts of the compounds of the present invention.

Active compounds of the present invention can be administered alone orin combination with other therapeutic agents. For example, activecompounds of the present invention can be coadministered with compoundsnow known, or later identified, to be useful for the prevention and ortreatment of viral infections and conditions such as septic shock,inflammation, organ damage, neurological disorders, neurodegenerativediseases, cancer, and cardiac disorders, ,and diseases associated withoverproduction of superoxide anion radical, TNF-α, and iNOS, Exemplarycompounds include, but are not limited to, analgesics, anesthetics,antifungals, antibiotics, antiinflammatories, anthelmintics, antidotes,antiemetics, antihistamines, antihypertensives, antimalarials,antimicrobials, antipsychotics, antipyretics, antiseptics,antiarthritics, antituberculotics, antitussives, antivirals,cardioactive drugs, cathartics, chemotherapeutic agents, corticoids(steroids), antidepressants, depressants, diagnostic aids, diuretics,enzymes, expectorants, hormones, hypnotics, minerals, nutritionalsupplements, parasympathomimetics, potassium supplements, sedatives,sulfonamides, stimulants, sympathomimetics, tranquilizers, urinaryantiinfectives, vasoconstrictors, vasodilators, vitamins, xanthinederivatives, and the like.

Opioid compounds and opioid-like compounds can have unwanted sideeffects in the central nervous system. Therefore, compounds of thepresent invention in which undesirable side effects are minimal tonon-existent are preferred.

A. Synthesis of Compounds

Variations on the following general synthetic methods will be readilyapparent to those of ordinary skill in the art and are deemed to bewithin the scope of the present invention.

A compound having the structural formula R-A-X, wherein A is an opioidskeleton having a structural formula such as shown in formula III, IV,VI or VII, and appropriate substituents or links among W, S, and T whichwould form a structure of formula III, IV, VI or VII, are preparedaccording to the reaction scheme shown below in which R and X, unlessotherwise indicated, are as defined above.

Compounds of formula XXIV are prepared by O-alkylation of a compound offormula XXIII in a base or a catalyst and a polar solvent with a halide,RZ. Z can be halides or a leaving group such as mesyl, tosyl, ortriflate. Suitable bases or catalysts include, but are not limited to,potassium carbonate, NaH, KH, sodium or potassium hexamethyldisilazide,and tertiary amines such as trialkylamines, for example, triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), and 1,5-iazabicyclo[4.3.0]non-5-ene (DBN). Suitable polar solvents include, butare not limited to, ethers, for examples, diethyl ether, glycol dimethylether, tetrahydrofuran, dioxane; acetone, dimethylformamide, toluene oracetonitrile. The reaction temperature can be from about roomtemperature to 150° C.

Compounds of formula XXIII can be prepared by demethylation of acompound of formula XXII with 47% HBr or BBr₃ in methylene chloride at atemperature from about −78° C. to 150° C.

Compounds of formula XXII can be prepared by N-alkylation of a compoundof formula XXI in a base or a catalyst and a polar solvent with XZ wherem ≠0. Z is as defined above. The base or the catalyst, the polar solventand reaction temperature is as defined above for the synthesis offormula XXIV from formula XXIII.

N-arylation of a compound of formula XXI with XZ where m=0 may beperformed using a palladium catalyst and CS₂CO₃ as the stoichiometricbase according to the methods which are described in Tet. Lett. 38,6359-6362 (1997) and Tet. Lett. 38, 6363-6366 (1997). X is R₄ whichrepresents an aryl group.

Compounds of formula XXI can be prepared by treating of formula XX in1,2-dichloroethane with 1-chloroethyl chloroformate and potassiumcarbonate in a temperature from 0° C. to a refluxing temperature in thepresence of nitrogen. Formula XX is a commercially available compound.

The present invention contemplates all enantiomers of compounds havingformula XXIV. In some embodiments, however, the configuration at C9 isthe S-configuration. In other embodiments, the S-configuration is alsopresent at C5 of compounds having formula III.

B. Pharmaceutically Acceptable Salts

The term “active agent” as used herein, includes the pharmaceuticallyacceptable salts of the compound. Pharmaceutically acceptable salts aresalts that retain the desired biological activity of the parent compoundand do not impart undesired toxicological effects. Examples of suchsalts are (a) acid addition salts formed with inorganic acids, forexample hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid and the like; and salts formed with organic acids suchas, for example, acetic acid, oxalic acid, tartaric acid, succinic acid,maleic acid, fumaric acid, gluconic acid, citric acid, malic acid,ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonicacid, and the like; and (b) salts formed from elemental anions such aschlorine, bromine, and iodine. In other particular embodiments,pharmaceutically acceptable salts are formed with malic acid. Inparticular embodiments, pharmaceutically acceptable salts are formedwith hydrochloric acid.

Active agents used to prepare compositions for the present invention mayalternatively be in the form of a pharmaceutically acceptable free baseof active agent. Because the free base of the compound is less solublethan the salt, free base compositions are employed to provide moresustained release of active agent to the target area. Active agentpresent in the target area which has not gone into solution is notavailable to induce a physiological response, but serves as a depot ofbioavailable drug which gradually goes into solution.

C. Pharmaceutical Formulations

The opioid and opioid-like compounds of the present invention are usefulas pharmaceutically active agents and may be utilized in bulk form. Morepreferably, however, these compounds are formulated into pharmaceuticalformulations for administration. Any of a number of suitablepharmaceutical formulations may be utilized as a vehicle for theadministration of the compounds of the present invention.

It will be appreciated that certain compounds of the above formulas canpossess an asymmetric carbon atom(s) and are thus capable of existing asenantiomers. Unless otherwise specified, this invention includes suchenantiomers, including racemates. The separate enantiomers may besynthesized from chiral starting materials, or the racemates can beresolved by procedures that are well known in the art of chemistry suchas chiral chromatography, fractional crystallization of diastereometricsalts and the like.

The compounds of the present invention may be formulated foradministration for the treatment of a variety of conditions. In themanufacture of a pharmaceutical formulation according to the invention,the compounds of the present invention and the physiologicallyacceptable salts thereof, or the acid derivatives of either (hereinafterreferred to as the “active compound”) are typically admixed with, interalia, an acceptable carrier. The carrier must, of course, be acceptablein the sense of being compatible with any other ingredients in theformulation and must not be deleterious to the patient. The carrier maybe a solid or a liquid, or both, and is preferably formulated with thecompound as a unit-dose formulation, for example, a tablet, which maycontain from 0.5% to 95% by weight of the active compound. In oneparticular embodiment, a pharmaceutical composition comprises less than80% by weight of active compound. In other particular embodiments, apharmaceutical composition comprises less than 50% by weight of activecompound. One or more of each of the active compounds may beincorporated in the formulations of the invention, which may be preparedby any of the well-known techniques of pharmacy consisting essentiallyof admixing the components, optionally including one or more accessoryingredients.

The formulations of the invention include those suitable for oral,rectal, topical, buccal (e.g., sub-lingual), parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous) andtransdermal administration, although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated and on the nature of the particular active compound which isbeing used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, tablets, dragees,or syrups each containing a predetermined amount of the active compound;as a powder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound and asuitable carrier (which may contain one or more accessory ingredients asnoted above).

In general, the formulations of the invention are prepared by uniformlyand intimately admixing the active compound with a liquid or finelydivided solid carrier, or both, and then, if necessary, shaping theresulting mixture. For example, a tablet may be prepared by compressingor molding a powder or granules containing the active compound,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent, and/or surface active/dispersingagent(s). Molded tablets may be made by molding, in a suitable machine,the powdered compound moistened with an inert liquid binder.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising the active compound in a flavoured base, usuallysucrose and acacia or tragacanth; and pastilles comprising the compoundin an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous preparations of theactive compound, which preparations are preferably isotonic with theblood of the intended recipient. These preparations may be administeredby means of subcutaneous, intravenous, intramuscular, or intradermalinjection. Such preparations may conveniently be prepared by admixingthe compound with water or a glycine buffer and rendering the resultingsolution sterile and isotonic with the blood.

Formulations suitable for rectal administration are preferably presentedas unit dose suppositories. These may be prepared by admixing the activecompound with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3(6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. Suitable formulations comprise citrateor bis\tris buffer (pH 6) or ethanol/water and contain from 0.01 to 0.2Mactive ingredient.

The present invention may also be formulated into a sustained-releasepreparation. A sustained-release composition includes, but is notlimited to, those in which the active ingredient is bound to an ionexchange resin which is optionally coated with a diffusion barrier tomodify the release properties of the resin.

Carriers and/or diluents which may be used include vaseline, lanoline,glycerin, vegetable oils, or fat emulsions, polyethylene glycols,alcohols, transdermal enhancers, natural or hardened oils or waxes, andcombinations of two or more thereof.

D. Methods of Use

In addition to the compounds of the formulas described herein, thepresent invention also provides useful therapeutic methods. For example,the present invention provides a method of treating viral infections andseptic shock, inflammation, organ damage, neurological disorders,neurodegenerative diseases, cancer, and cardiac disorders, and diseasesassociated with overproduction of superoxide anion radical, TNF-a, andiNOS. In some embodiments, viral infections include, but are not limitedto, infections by Hepatitis B virus and Hepatitis C virus.

In particular embodiments, organ damage includes, but is not limited to,liver damage, kidney damage, and lung damage. Such damage may arise fromcauses that include, but are not limited to, alcohol abuse, cirrhosis,hepatitis, and septic shock such as sepsis arising from bacterialinfections or environmental toxins such as carbon tetrachloride.

In other particular embodiments, neurological disorders include, but arenot limited to seizure disorders such as epilepsy, Tourette Syndrome,stroke, and neurodegenerative diseases including, but not limited to,Parkinson's disease, Alzheimer's disease, cognition deficit disorder,memory loss, amyotrophic lateral sclerosis, and multiple sclerosis.

In particular embodiments, exemplary cancers include, but are notlimited to, leukemia, lymphoma, colon cancer, renal cancer, livercancer, breast cancer, lung cancer, prostate cancer, ovarian cancer,melanoma, small cell lung cancer, testicular cancer, esophageal cancer,stomach cancer, endometrial cancer, central nervous system cancer, andthe like. The term “cancer” has its understood meaning in the art, forexample, an uncontrolled growth of tissue that has the potential tospread to distant sites of the body (i.e., metastasize). Preferred aremethods of treating and preventing tumor-forming cancers. The term“tumor” is also understood in the art, for example, as an abnormal massof undifferentiated cells within a multicellular organism. Tumors can bemalignant or benign. Preferably, the inventive compounds and methodsdisclosed herein are used to prevent and treat malignant tumors.

In still yet other particular embodiments, cardiac disorders include,but are not limited to, cardiac ischemia, congestive heart failure, andhypertension.

In other particular embodiments, diseases associated with overproductionof superoxide anion radical, TNF-α, or iNOS include, but are not limitedto, Alzheimer's disease, Parkinson's disease, aging, cancer, myocardialinfarction, atherosclerosis, autoimmune disease, radiation injury,emphysema, sunburn, joint disease, and oxidative stress. Suitablesubjects to be treated according to the present invention include bothavian and mammalian subjects, preferably mammalian. Mammals according tothe present invention include but are not limited to canine, felines,bovines, caprines, equines, ovines, porcines, rodents (e.g. rats andmice), lagomorphs, primates, and the like, and encompass mammals inutero. Humans are preferred.

Illustrative avians according to the present invention include chickens,ducks, turkeys, geese, quail, pheasant, ratites (e.g., ostrich) anddomesticated birds (e.g., parrots and canaries), and include birds inovo. Chickens and turkeys are preferred.

Any mammalian subject in need of being treated according to the presentinvention is suitable. Human subjects are preferred. Human subjects ofboth genders and at any stage of development (i.e., neonate, infant,juvenile, adolescent, adult) can be treated according to the presentinvention.

As noted above, the present invention provides pharmaceuticalformulations comprising the compounds of formulae described herein, orpharmaceutically acceptable salts thereof, in pharmaceuticallyacceptable carriers for any suitable route of administration, includingbut not limited to, oral, rectal, topical, buccal, parenteral,intramuscular, intradermal, intravenous, and transdermal administration.

According to the present invention, methods of this invention compriseadministering an effective amount of a composition of the presentinvention as described above to the subject. The effective amount of thecomposition, the use of which is in the scope of present invention, willvary somewhat from subject to subject, and will depend upon factors suchas the age and condition of the subject and the route of delivery. Suchdosages can be determined in accordance with routine pharmacologicalprocedures known to those skilled in the art. For example, the compoundsof the present invention can be administered to the subject in an amountranging from a lower limit from about 0.01, 0.02, 0.03, 0.04, 0.05,0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80,0.90, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10% to an upperlimit ranging from about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, or 100% by weight of the composition. In someembodiments, the compounds comprise from about 0.05 to about 95% byweight of the composition. In other embodiments, the compounds comprisefrom about 0.05 to about 60% by weight of the composition. In stillother embodiments, the compounds comprise from about 0.05 to about 10%by weight of the composition.

The therapeutically effective dosage of any specific compound will varysomewhat from compound to compound, patient to patient, and will dependupon the condition of the patient and the route of delivery. As ageneral proposition, a dosage from about 0.1 to about 50 mg/kg will havetherapeutic efficacy, with still higher dosages potentially beingemployed for oral and/or aerosol administration. Toxicity concerns atthe higher level may restrict intravenous dosages to a lower level suchas up to about 10 mg/kg, all weights being calculated based upon theweight of the active base, including the cases where a salt is employed.Typically a dosage from about 0.5 mg/kg to about 5 mg/kg will beemployed for intravenous or intramuscular administration. A dosage fromabout 10 mg/kg to about 50 mg/kg may be employed for oraladministration.

In particular embodiments, compounds of the present invention may beadministered at a daily dosage of from about 0.1 mg to about 20 mg perkg of animal body weight, which can be given in divided doses q.d. toq.i.d. or in a sustained release form. For humans, the total daily dosemay be in the range of from about 5 mg to about 1,400 mg, and in otherparticular embodiments, the total daily dose is in the range of fromabout 10 mg to about 100 mg. In still other embodiments, the unit dosageforms suitable for oral administration may comprise about 2 mg to about1,400 mg of the compound optionally admixed with a solid or liquidpharmaceutical carrier or diluent. The compounds of the presentinvention can be administered in any amount appropriate to administer tothe subject for treatment of the condition desired to be treated asdetermined by one of ordinary skill in the art by reference to thepertinent texts and literature and/or by using routine experimentation.(See, for example, Remington, The Science And Practice of Pharmacy (9thEd. 1995). However, in general, satisfactory results are obtained whenthe compounds of the invention are administered at a daily dosage offrom about 0.1 mg to about 20 mg per kg of animal body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form.

The present invention is explained in greater detail in the followingnon- limiting examples.

Example 1 (+)-3-methoxy-17-allylmorphinan hydrobromide

A solution of 1.0 g (3.41 mmol) of (+)-3-methoxy-morphinan hydrochloridein tetrahydrofuran (THF) (20 mL) was added to triethylamine 1.3 mL(10.26 mmol). After stirring for 30 minutes, allyl bromide 0.52 mL (6.82mmol) was added. The resulting mixture was stirred for 8 hours at roomtemperature (20-25° C.). Then the mixture was evaporated and partitionedwith CH₂Cl₂ (40 mL) and water (20 mL). The CH₂Cl₂ layer was separated,dried over MgSO₄, and evaporated to afford crude product (700 mg). Theyield was 69%. The crude product was dissolved in CH₂Cl₂ (15 mL), andthen 48% hydrobromic acid (0.5 mL) was slowly added with stirring over10 min. The solution was evaporated and pump dried. The crude wasrecrystallized from ethyl acetate to afford HBr (560 mg) as light yellowpowder. Total yield was 63%; mp 190-192° C.; mass spectroscopy recordedon a Finnigan MAT95S mass spectrometer: MS (EI, 70 eV) m/z 297 (M⁺),270; HRMS calculated for C₂₀H₂₇NO⁺: 297.2093, found: 297.2087.

Example 2 (+)-3-methoxy-17-benzylmorphinan hydrobromidc

A solution of 1.0 g (3.41 mmol) of (+)-3-methoxy-morphinan hydrochloridein THF (20 mL) was added to triethylamine 0.88 mL (6.84 mmol). Afterstirring for 30 min., benzyl bromide 0.40 mL (3.41 mmol) was added. Theresulting mixture was stirred for 6 hours at room temperature. Then themixture was evaporated and partitioned with CH₂Cl₂ (40 mL) and water (20mL). The CH₂Cl₂ layer was separated, dried over MgSCO₄, and evaporatedto afford crude product. The crude product was chromatographed(CH₂Cl₂:MeOH=15:1) to get yellow liquid. The liquid was dissolved inCH₂Cl₂ (15 mL), and then 48% hydrobromic acid (0.5 mL) was slowly addedwith stirring over 10 min. The solution was evaporated and dried withpump. The crude was recrystallized from CH₂Cl₂ and ethyl acetate toafford 3 HBr (560 mg) as light yellow crystals. Total yield was 38%; mp185-186° C; MS (EI 70 eV) m/z 347 (M⁺), 226; HRMS calculated forC₂₄H₂₉NO⁺: 347,2249, found: 347.2227.

Example 3 (+)-3-methoxy-17-(4-fluorobenzyl)morphinan hydrobromide

A solution of 1.0 g (3.41 mmol) of (+)-3-methoxy-morphinan hydrochloridein THF(20 mL) was added to triethylamine 0.88 mL (6.84 mmol). Afterstirring for 30 min., 4-fluorobenzyl bromide 0.42 mL (3.41 mmol) wasadded. The resulting mixture was stirred for 20 hours at roomtemperature. Then the mixture was evaporated and partitioned with CH₂Cl₂(40 mL) and water (20 mL). The CH₂Cl₂ layer was separated, dried overMgSO₄, and evaporated to afford crude product. The crude product waschromatographed (CH₂Cl₂:MeOH=15:1) to get colorless liquid. The liquidwas dissolved in CH₂Cl₂ (15 mL), and then 48% hydrobromic acid (0.5 mL)was slowly added with stirring over 10 min. The solution was evaporatedand pump dried. The crude was recrystallized from ethyl acetate toafford HBr (980 mg) as colourless crystals. Total yield was 64%; mp226-228° C.; MS(EI,7 OeV) m/z 365(M⁺); HRMS calculated for C₂₄H₂₈FNO⁺:365.2155, found: 365.2146.

Example 4 (+)-3-Methoxy-17-(trans-cinnamylbenzyl)morphinan hydrobromide

A solution of 1.0 g (3.41 mmol) of (+)-3-methoxy-morphinan hydrochloridein THF (20 mL) was added to triethylamine 0.88 mL (6.84 mmol). Afterstirring for 30 min., cinnamyl bromide 0.64 mL (3.41 mmol) was added.The resulting mixture was stirred for 19 hours at room temperature. Thenthe mixture was evaporated and partitioned with CH₂Cl₂ (40 mL) and water(20 mL). The CH₂Cl₂ layer was separated, dried over MgSO₄, andevaporated to afford crude product. The crude product waschromatographed (CH₂-Cl₂:MeOH=15:1) to get yellow liquid. The crudeliquid was dissolved in CH₂Cl₂ (15 mL), and then 48% hydrobromic acid(0.5 mL) was slowly added with stirring over 10 min. The solution wasevaporated and pump dried to afford compound HBr as yellow foam liquid.MS (EI, 70 eV) m/z 373 (M⁺); HRMS calculated for C₂₆H₃,NO⁺: 373.2406,found: 373.2388.

Example 5 (+)-3-methoxy-17-(3-pyridylmethy)morphinan hydrobromide

Similarly to the preparation of Example 4, the title compound wasprepared from the reaction of (+)-3-methoxy-morphinan hydrochloride (1g, 3.4 mmol) in THF (20 ml), triethylamine (1.43 ml, 10.3 mmol), and3-(bromomethyl)pyridine hydrobromide (0.95 g, 3.75 mmol) gave a solidwhich was treated with 45% HBr to afford 1 g of a tan solid (68% yield);ms(ESR): m/z 349 (M+1).

Example 6 (+)-3-methoxy-17-(2-thienylmethyl)morphiaan hydrobromide

Similarly to the preparation of the above examples, the title compoundis prepared from (+)-3-methoxy-morphinan hydrochloride in THF (20 ml),triethylamine 0.88 mL (6.84 mmol), 2-thienylmethanol mesylate (3.41mmol).

2-thienylmethanol mesylate is prepared by treating a solution of2-thienylmethanol (5.57 g; 50 mmol)in methylene chloride (100 ml) andtriethylamine (15.05 g, 150 mmol) at 0° C. with methanesulfonyl chloride(11.45 g, 100 mmol) dropwise and at RT 1 hr after the addition. Thereaction mixture is poured into ice-water and the organic layer isseparated, dried (MgSO4), and evaporated.

Example 7 (+)-3-methoxy-17-acetyl-morphinan

Acetic anhydride (3.14 g, 30.76 mmol) was added to a solution of(+)-3-methoxy-morphinan hydrochloride (1.5 g, 5.1 mmol) in THF (30 ml)and triethylamine (8.7 g, 85.98 mmol) in the presence of nitrogen. Theresulting solution was heated at 60° C. for 15 hr. The reaction mixturewas cooled to room temperature and evaporated under vacuum. The residuewas dissolved in methylene chloride (50 ml), washed with water (40 ml×2)and dried (MgSO4). Evaporation of the dried solution gave a tan viscousoil (1.25 g, 81% yield); ms (ESI+): m/z 300(M+1).

Example 8 (+)-3-methoxy-17-trans-crotonyl-morphinan

Thionyl chloride (18.3 ml) was added to a solution of trans-crotonicacid (20 g) in toluene (5 ml) and stirred. The resulting solution wasstirred at a temperature below 10° C. for 4 hr and thereafter thionylchloride was distilled off. The residue was evaporated under vacuum togive a brown residue of crotonyl chloride and used directly. A solutionof (+)-3-methoxy-morphinan hydrochloride (0.5 g, 1.5 mmol) in toluene(15 ml) and triethylamine (0.5 ml, 3.5 mmol) was stirred for 5 min andtic (Ethyl acetate: hexane=1:1) indicated that the reaction wascomplete. The reaction mixture was washed with water (200 ml) and theorganic layer was evaporated under vacuum. This gave a viscous oil. Theoil was further purified by a silica gel column eluting with ethylacetate:hexane (1:1) to give a light tan oil; ms (ESI+): m/z 362 (M+1).

Example 9 (+)-3-methoxy-17-(indole-5-carbonyl)-morphinan

Oxalyl chloride (15 ul, 0.14 mmol) at RT was added to a solution ofindole-5-carboxylic acid (0.02 g, 0.12 mmol) in THF (1 ml). Afterstirring at RT for 10 h, the mixture was added THF (1 ml) followed by(+)-3-methoxy-morphinan hydrochloride (0.04 g, 0.12 mmol), thentriethylamine (0.1 ml, 0.7 mmol) was added and stirred for 18 h. Thereaction mixture was filtered and washed with ethyl acetate. Thefiltrate was washed with saturated Na₂CO₃ (5 ml), dried (Na₂SO₄),filtered and concentrated at reduced pressure to give a crude pale brownoil. The crude product was purified by column chromatographed elutingwith (MeOH: CH2Cl2=1:10) to give a pale yellow oil (0.013 g, 28% yield).

Example 10 (+)-3-methoxy-17-(indole-5-methyl)-morphinan

Lithium aluminum hydride (1 M in THF; 0.1 ml, 0.1 mmol) was added to asolution of the amide, Example 9, (0.013 g, 0.033 mmol) in THF (1 ml) at0° C. The mixture was heated at reflux for 5 h, then was cooled to 0°C., and treated with 3% aq NaOH (1.5 ml). The mixture was filteredthrough a pad of Celite and the filtrate was dried over anhyd. Na₂SO₄,and evaporated the dried solution to give a pale yellow oil (0.010 g);MS(EI): m/z 402 (M)

Example 11 (+)-3-methyl-17-methyl-morphinan

(+)-1-p-methylbenzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline(26.5 g) was added to 85% phosphoric acid (130 ml) and the mixture washeated to 130-140° C. for 72 h. After the reaction was complete, thereaction mixture was poured into ice-water and the solution was madestrongly alkaline by the addition of conc. ammonia solution (about 300ml) and diluted with water (500 ml). The solution was then extractedwith ether (500 ml×2). The ether layers were combined and washed withwater (200 ml), and dried (K₂CO₃), filtered and evaporated to yield anoil. The oil was immediately vacuum- distilled to produce a faint yellowoil (10 g; bp 130-136° C./0.3 mm Hg) which was crystallized on standing.Recrystallization from acetone (˜10 ml) provided white prisms ((7.3 g)of (+)-3-methyl-17-methyl-morphinan; MS(ESI+): m/z 256 (M+1). Thisprocedure is similar to the procedure in U.S. Pat. No. 3,786,054,incorporated by reference herein in its entirety.

Example 12 (+)-3-methoxy-17-[2-(1-azabicyclo[2.2.1]heptanyl)]morphinanHydrobromide

A solution of 1.0 g (3.41 mmol) of (+)-3-methoxy-morphinan hydrochloridein anhyd. hexamethylphosphrous triamide (20 mL ) and triethylamine 0.88mL (6.84 mmol) is stirred at room temperature for 30 min. The resultingmixture is treated with 2-bromo-1-azabicyclo[2.2.1]heptane (0.60 g, 3.41mmol) and heated under reflux for 48 hr. Then the mixture is cooled,diluted with ethyl acetate (100 ml), washed with water (20 ml×3) andsaturated brine (10 ml), dried (MgSO₄) and evaporated to afford an oil.The oil product is purified through a silica gel column (CH₂Cl₂:MeOH=15:1) to give a free base of the title compound. To a solution ofthe purified product in CH₂Cl₂ is added slowly 48% hydrobromic acid (0.5mL) with stirring over 10 min. The solution is evaporated and driedunder high vacuum to afford the HBr salt of the title compound.

Example 13 (+)-3-methoxy-17-(4-nitrophenyl)morphinan

Pd(OAc)2 (1.34 mg, 0.006 mmol) and 10% solution of P(t-Bu)₃ in hexane(0.015 ml, 0.0048 mmol) were added to the suspension of NaO-t-Bu (86.4g, 0.9 mmol), (+)-3-methoxy-morphinan (0.1645 g, 0.5 mmol) and4-(nitro)-bromobenzene (0.1212 g, 0.6 mmol) in toluene (˜12 mL) in thepresence of nitrogen. The resulting mixture was heated at 80° C. for 6h. The reaction mixture was allowed to cool to room temperature, dilutedwith methylene chloride (50 mL), and washed with water. Concentration ofthe organic layer and flash chromatography on silica gel was carried outeluting with hexane first and then with a 5% to 20% ethyl acetatesolution in hexane to provide a yellow liquid, 56.4 mg (30% yield); ms(EI): m/z 378 (M).

Example 14 (+)-3-methoxy-17-(quinuclidinyl-3-carbonyl)-morphinan

Similar to the preparation of indole-5-carboxyl chloride, 1-azabicyclo[2.2.2.]octane-3-carboxylic acid or quinuclidinyl-3-carboxylicacid or compounds described in Orlek, B. S. et al, J. Med. Chem. 34(9),2726-2735 (1991) are converted to quinuclidinyl-3-carboxyl chloride. Thechloride is allowed to react with (+)-3-methoxy-morphinan hydrochlorideas described in the preparation of Example 9 to provide the titlecompound as shown below.

Example 15 (+)-3-methoxy-17-(quinuclidinyl-3-methyl)-morphinan

The compound is synthesized by treating the amide from Example 13 withlithium aluminum hydride in a manner similar to the preparation ofExample 10. The resulting compound is shown below.

Example 16 (+)-3-methoxy-17-(phenyl)morphinan

Similar to the preparation of the compound of Example 13, the titlecompound is made from the reaction of Pd(OAc)₂ (1.34 mg, 0.006 mmol),10% solution of P(t-Bu)₃ in hexane (0.015 ml, 0.0048 mmol), and NaO-t-Bu(86.4 g, 0.9 mmol) in the presence of argon and then a solution of(+)-3-methoxy-morphinan (0.1645 g, 0.5 mmol) and bromobenzene (0.094 g,0.6 mmol) in toluene (˜12 mL).

Example 17 Pharmacological Testing

The pharmacological activity of the compounds of the present inventionmay be measured in the tests set out below.

In vivo Experiments

Wistar-Kyoto (WKY) rats were anesthetized by intraperitoneal injectionof urethane (1.2 g/kg). The trachea was cannulated to facilitaterespiration and environmental temperature was maintained at 24° C. withan air-conditioning system. The right carotid artery was cannulated andconnected to a pressure transducer (P231D, Statham, Oxford, Calif.) forthe measurement of phasic blood pressure and mean arterial bloodpressure (MAP) as well as heart rate (HR), which were displayed on aGould model TA5000 polygraph recorder (Gould Inc., Valley View, Ohio).The left jugular vein was cannulated for the administration of drugs.Upon completion of the surgical procedure, cardiovascular parameterswere allowed to stabilize for 30 min. After recording baselinehemodynamic parameters, animals were given norepinephrine [NE, 1 μg/kgintravenously (i.v.)], and 10 min later animals received vehicle(saline) or Escherichia coli lipopolysaccharide (LPS), 5-10 mg/kg, i.v.and were monitored for 360 min. The pressor responses to NE werereassessed every hour after vehicle or LPS injection. Prior to (i.e., attime 0) and every hour after vehicle or LPS, 0.5 mL of blood was takento measure the changes in cytokine tumor necrosis factor-α (TNF-α),interleukin-10β (IL-10), and nitrate (an indicator of NO) (Yen, M. H. etal., Shock 14, 60-67, 2000). Any blood withdrawn was immediatelyreplaced by the injection of an equal volume of saline (i.v.) in orderto maintain the blood volume. The drug was administered i.v. 30 min.prior to and 30 min. after the injection of LPS. All hemodynamic andbiochemical parameters were recorded for 6 hours in all animal groups.

Measurement of TNF-α and IL-10 in Plasma Levels

Blood samples (0.3 mL) for the measurement of TNF-α level in the plasmawere obtained at 0, 60, 120, 180, and 360 min. after the injection ofsaline or LPS. At 60 and 360 min. after the injection of saline or LPS,the volume of blood sample taken from the animals was 0.5 mL instead of0.3 mL for performing the measurement of IL-10 in addition to TNF-α.These samples were collected from a catheter placed in the carotidartery and were centrifuged at 7200 g for 3 min. to obtain the plasmafor measuring the levels of TNF-α, IL-10, and nitrate (as describedbelow). The plasma samples (100 μL) were diluted 1:2, and TNF-α wasmeasured in duplicate with an enzyme-linked immunoadsorbent assay(ELISA) kit (Genzyme Co., Cambridge, Mass.), and the amounts of IL-10 inthe plasma (100 μL) were measured by ELISA kit (Endogen Inc., Boston,Mass.), as described previously (Yen, M. H. et al.: Biochem. Biophys.Res. Commun. 228:459-466 (1996)).

Determination of Plasma Nitrate

Fifty microliters of plasma previously kept in −20° C. freezer wasthawed and de-proteinized by incubating with 95% ethanol (4° C.) for 30min. The samples were subsequently centrifuged for an additional 5 min.at 14,000 g. It is noted that the nitrate concentration in plasmadepicted in the study is actually the total nitrite and nitrateconcentration in plasma. In this method, nitrate is reduced to NO vianitrite. The amounts of nitrate in the plasma (2 p.L) were measured byadding a reducing agent (0-8% VCl₃ in 1N HCl) to the purge vessel toconvert nitrate to NO, which was stripped from the plasma by using ahelium gas purge. The NO was then drawn into the Sievers Nitric OxideAnalyzer (Sievers 280 NOA, Sievers Inc., Boulder, Colo.). Nitrateconcentrations were calculated by comparison with standard solutions ofsodium nitrate (Sigma Chemical Co., St. Louis, Mo.).

Measurement of Serum Glutamic Oxaloacetic Transaminase (SGOP) and SerumGlutamicpyrate Transaminase (SGTP)

10 μl of serum was taken out at 0 and 6 hr intervals and were added toslides of GOP and GTP and then placed in DRI-CHEM 3000(Colorige TrieAnalyzer; FUJIFILM; Tokyo, Japan

Determination of Blood Urea Nitrogen (BUN) and Plasma Creatinine

BUN and Creatinine levels were measured at 0 and 6 hr afer injection ofsaline or LPS by “DRI-Chemical slide” (Fujifilm Co., dropping 10 μLplasma onto the slide with micropipette).

Survival Studies

Survival studies were performed in ICR mice (28-35 g), whose stockoriginated from the Institute of Cancer Research of National Instituteof Health in U.S.A. They were purchased from the National Animal Center(Taipei, R.O.C., Taiwan). LPS [60 mg/kg intraperitoneally (i.p.)] wasinjected in the presence of vehicle or drugs and survival was monitoredevery 6 hours until 36 hours. Different groups of animals receivedvehicle (saline) together with LPS (n=20) or LPS plus compounds (2.5mg/kg at time 0 and 6 hours after LPS, n=20).

Histological Studies

Lungs and livers were obtained from surviving mice in each group afterthe survival study and these tissues were fixed in Carson-Millonig'ssolution for histopathological examination as described previously inChen, A. et al. Lab. Invest. 67, 175-185 (1992). The fixed lung andliver tissues were dehydrated in graded ethanol and embedded inparaffin. Three-micron sections were stained with the hematoxylin andeosin reagent for light microscopy. In preliminary experiments, astriking pathological feature of the mice receiving LPS was a prominentinfiltration of neutrophils in the organs studied. This histologicalalteration was quantitatively analyzed as an index on the severity oftissue injury. This index was a neutrophil infiltration index which wasdetermined by counting the numbers of neutrophils in 10 randomlyselected high power fields. The index was expressed as the mean of these10 numbers±standard error of the mean (SEM)/high power field.

Statistical Analysis

AH values in the FIGS. and text are expressed as mean. SEM of nobservations, where n represents the number of animals studied.Statistical evaluation was performed by using analysis of variance(ANOVA) followed by a multiple comparison test (Scheffe's test), theIL-10 level and the neutrophil infiltration index which were analyzed byunpaired Student's t test. The chi-square test was used for determiningthe significant differences in the survival rate between control anddrug-treated groups. A P value of less than 0.05 was considered to bestatistically significant.

Example 18 Serum Glutamic Oxaloacetic Transaminase (SGOT)

At 0 hr, the average of SGOT in the control group was 60±6 U/L. Whenanimals were given LPS, the plasma concentration of the SGOT increasedas a function of time. XXV (R=methyl, A=V, X=cyclopropylmethyl) (shownbelow)

exhibited significant decrease (p□0.05) of SGOT 6 hours after LPSadministration in both pretreatment (30 min before LPS; 5, 10 mg/kg) andpost-treatment (30 min after LPS; 10 mg/kg) groups.

Example 19 Serum Glutamic Pyrate Transaminase (SGPT)

At 0 hr, the average of SGTP in the control group was 30±4 U/L. Whenanimals were given LPS, the plasma concentration of the SGTP increasedas a function of time. Similarly, XXV exhibited a significant decrease(p□0.05) of SGTP 6 hours after LPS administration in both pretreatment(30 min before LPS; 5, 10 mg/kg) and post-treatment (30 min after LPS;10 mg/kg) groups.

Example 20 Results

Compounds, XXV and XXVI (shown below), were tested according to theforegoing protocols. The results are summarized in Table 1 as shownbelow. In the following tables, XXV or XXVI (5 mg/Kg, iv) was injected30 min before LPS treatment (10 mg/Kg, iv) unless otherwise indicated.In all experiments, at least six rats were tested. All measurements wereperformed 6 h after LPS injection unless otherwise indicated. Theinhibitory effects of the compounds tested were described as apercentage of protection or inhibition with respect to the change inLPS-treated animals as compared to the control animals.

TABLE 1 Cardiovascular Effects Compound LPS + % Parameters # Control LPSCompound Protection MAP(mmHg) XXV 105 60 80  33 XXVI 105 58 105 100Heart Rate XXV 430 355 410   >90% (beats/min) XXVI 384 440 420   36%

TABLE 2 Free Radicals and TNF-α Compound LPS + % Parameters # ControlLPS Compound Inhibition Superoxide XV 8500 31572 11866 85 (relative (10mg)² units) XV 8500 31572 15720 69 (10 mg)³ XXVI 4500 15800 8200 68Nitrate (uM) XXVI 30 180 75 75 TNF- XXV 60 300 180 50 α (ng/ml)¹ XXVI 401800 510 74 ¹The measurement was taken at 2 h. ²Pretreatment with 10mg/Kg. ³Post-treatment with 10 mg/Kg.

TABLE 3 Liver Functions Compound LPS + % Parameters # Control LPSCompound Inhibition SGOT(U/L) XXV 105 328 192 60 XXV 105 328 192 94 (10mg/Kg)¹ XXV 105 328 192 76 (10 mg/Kg)² XXVI 118 286 158 53 SGPT(U/L) XXV51.4 98 61.6 78 XXV 51.4 98 53.8 94 (10 mg/Kg)¹ XXV 51.4 98 559.6 82 (10mg/Kg)² XXVI 38 42 36 100³   ¹Pretreatment with 10 mg/Kg.²Post-treatment with 10 mg/Kg. ³Not statistically significant.

TABLE 4 Kidney Function Compound LPS + % of Parameters # Control LPSCompound Inhibition Blood urine XXVI 30 58 45 47 nitrogen (mg/dL)Creatinine XXVI 0.28 0.58 0.40 60 mg/dL)

TABLE 5 Mortality Compound LPS + % of Parameters # Control LPS CompoundProtection % of Survival XXVI 100 38 100 100 at 14 h % of Survival XXVI100 0 40 40 at 18 h

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1.

A is a structure selected from the group consisting of the followingstructures:

, and X is attached to the nitrogen atom, and is selected from the groupconsisting of hydrogen, allyl, cinnamoyl, crotonyl, (CH₂)C₆H₅-4F, phenylor substituted phenyl wherein phenyl is substituted with alkyl, NO₂,CF₃,or OCH₃, (CH₂)_(n)C°CR₃, (CH₂)_(n)R₅, and (CH₂)_(m)CHR₆R₇, wherein, n orm is from 0 to 6, R₃ is the same as R₄, wherein R₄ is defined above andR₅ is H, alkyl, CN, COR_(S), or structures selected from the groupconsisting of the following structures:

wherein Y is N; R₆ and R₇ are each independently H, or the same as R₄ asdefined above, R₃ is alkyl, or the same as R₄ as defined above; orenantiomers, diastereoisomers, or pharmaceutically acceptable salts,provided that i) where A is of structure V, or Vb, (a) R is not hydrogenwhen X is hydrogen, methyl, ally methyl-ethynyl; or an ethylene-nitrilegroup (b) R is not methyl or ethyl when X is methyl; (c) R is not benzylwhen X as methyl; (d) R is not methyl or acetyl and X is hydrogen; (e) Ris hydrogen, methyl and X is phenyl.
 2. (canceled)
 3. (canceled) 4.(canceled)
 5. A method of treating organ damage selected from the liverdamage and kidney damage, comprising administering to a subject in needthereof a therapeutically effective amount, at a daily dose of from 2 mgto 100 mg, of a compound of claim
 1. 6. (canceled)
 7. (canceled) 8.(canceled)
 9. A method of treating a disease associated withoverproduction of TNF-α selected from the group consisting of Crohn'sdisease, ulcerative colitis, organ failure, and pulmonary fibrosis,comprising administering to a subject In need thereof a therapeuticallyeffective amount, at a daily dose of from 2 mg to 100 mg, of a compoundof claim
 1. 10. A method of treating a disease associated withoverproduction of TNF-α selected from the group consisting of ulcerativecolitis, organ failure, and pulmonary fibrosis, comprising administeringto a subject in need thereof a therapeutically effective amount, at adaily dose of from 2 mg to 100 mg, of naltrexone or nalmefene. 11.(canceled)
 12. The method of treating liver or kidney damage, wherein apharmaceutical composition comprising naltrexone or nalmefene isadministered in combination with at least one other therapeutic agentselected from the group consisting of antibiotics, antimicrobials,antivirals, vaccines, interferons, and the like.
 13. A method oftreating HBV viral infections, comprising administering to a mammal inneed thereof a therapeutically effective amount of a compound asspecified in claim
 1. 14. A method of inhibiting tumor necrosis factoralpha in a mammal having need of such inhibition which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount, at a daily dose of from 2 mg to 100 mg, of a compound asspecified in claim
 1. 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. Amethod of treating mammals suffering from a pathological conditionrelated to autoimmunity which comprises administering to a mammal inneed thereof a therapeutically effective amount, at a daily dose of from2 mg to 100 mg, of a compound as specified in claim 1 as a tumornecrosis factor alpha inhibitor.
 19. A method of treating mammalssuffering from an inflammatory disease related to autoimmunity whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount, at a daily dose of from 2 mg to 100 mg, of a compoundas specified in claim 1 as an inducible nitrous oxide synthaseinhibitor. 20-34. (canceled)
 35. A method of treating ulcerative colitisas in claim 4, comprising administering to a subject in need thereof, apharmaceutical composition comprising a therapeutically effective amountof a compound of naltrexone or nalmefene.
 36. A method for treatingulcerative colitis as in claim 10, comprising administering to a subjectin need thereof, a pharmaceutical composition comprising a daily dose offrom 2 mg to 100 mg of naltrexone or nalmefene.
 37. The method of claim5, 9, 10, 11, 12, 13, 14, 18 or 19, wherein the pharmaceuticalcomposition is administered orally,
 38. The method of claim 5, 9, 10,11, 12, 13, 14, 18 or 19, wherein the pharmaceutical composition isadministered parenterally.